I am slightly puzzled by this contribution of Jeremy's since I thought  his own article was about the epistemological (non) advantages of placebo-controlled trials. My recollection is that he disputed there was such an advantage (a point of view I don't share). This debate seems to me to be somewhat orthogonal to the funding of me-toos etc.

Part of the problem with banning me-toos as clinical trials is that unless you know what the result will be you don't know what will be a me-too. Also, it is often a matter of degree:  since we have diuretics, are beta-blockers a me-too? Since we have beta-blockers are ACE inhibitors a me-too?

The cure here it seems to me is in re-imbursement strategies. We should have a policy that encourages price competition (my friends in pharma might hate me for saying this). We don't. The problem is the economic model. After all when it comes to generics (what some might consider the perfect me-too) then we surely are all in favour. (Although my own experience in formulation switches has taught me that things that ought to be the same can be surpisingly different.)

However, I do agree with Jeremy that "Finally, non-inferiority trials present an ethical problem for the clinician" or at least that this often true. It is precisely for this reason that placebo-controlled trials are the only acceptable trial where a) the disease is serious b) there is a partially effective remedy. Then placebo-controlled trials as an add-on is what must be used.

See Senn, S. (2009). "Placebo Misconceptions." American Journal of Bioethics 9(9): 53-54.
	
Regards

Stephen


Stephen Senn

Professor of Statistics
School of Mathematics and Statistics
Direct line: +44 (0)141 330 5141
Fax: +44 (0)141 330 4814
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________________________________________
From: Evidence based health (EBH) [[log in to unmask]] On Behalf Of Jeremy Howick [[log in to unmask]]
Sent: 15 July 2011 14:30
To: [log in to unmask]
Subject: Re: solution to health care cost crisis: technical vs.philosphical..

Dear Ben,

Thanks for sending this interesting article around. There is a much easier, and arguably more effective solution to unsustainably rising healthcare costs:

STOP FUNDING 'ME TOO' INTERVENTIONS THAT OFTEN COST 10-30 TIMES MORE THAN ESTABLISHED THERAPIES

See the following study for details:
Morgan, S. G., K. L. Bassett, J. M. Wright, R. G. Evans, M. L. Barer, P. A. Caetano, and C. D. Black. 2005. ""Breakthrough" drugs and growth in expenditure on prescription drugs in Canada." Bmj no. 331 (7520):815-6.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16141448


To anticipate allow me to respond to some well rehearsed but unthoughtful objections (see Howick 2009: http://www.informaworld.com/smpp/ftinterface~db=all~content=a914187206~fulltext=713240928)


<http://www.informaworld.com/smpp/ftinterface~db=all~content=a914187206~fulltext=713240928>The justification for non-inferiority trials is (Senn 2005; Piaggio et al. 2006):

 1.  The new treatment might have fewer side effects.
 2.  The new treatment could be cheaper or less invasive
 3.   the new treatment may be necessary in case people develop resistance to existing therapies.

1.Comparisons of side effects are often made carelessly. Existing treatments have usually been around for longer, so there will be more extensive data about their side effects. Certainly rare and long-term side effects of the new treatment will be relatively under-studied. Thus comparisons between the side effects of newer and older treatments are often unbalanced. In addition, if the new treatment has a better side effect profile, then we should conduct a superiority test of the relevant side effects. It is, of course, possible to run a superiority test for the side effects of interest and a non-inferiority test for the main outcome simultaneously. Then, if the new treatment is supposed to be more tolerable because it is less invasive or more convenient—say it involves one daily dose instead of two—then the benefits of the new regimen should result in a superior outcome (Garattini and Bertele 2007). For instance, we would expect participants taking one dose per day to adhere better to the regime. The superior adherence should translate to better outcomes. If not, then it is unclear whether the apparent improved convenience is of any value. At least in principle, apparently less convenient or more invasive regimes could improve the primary outcome, perhaps by enhancing the ‘placebo’ response.


Next, even if we allow some non-inferior treatments in case people develop resistance to our existing therapies or an unexpected side effect is discovered, it does not follow that we need dozens of similar therapies. Yet, dozens of roughly equivalent treatments is just what indiscriminate use of non-inferiority trials encourages. For instance, there are currently more than six SSRI antidepressants, andnumerous other pharmaceutical antidepressants (tricyclic agents, monoamine oxidase inhibitors (MAOIs), serotoninnorepinephrine reuptake inhibitors (SNRIs), noradrenergic and specific serotonergic antidepressants (NASSAs), norepinephrine (noradrenaline) reuptake inhibitors (NRIs), and norepinephrine-dopamine reuptake inhibitors). In addition there are many non-pharmaceutical treatments used to treat depression, including St. John’s wort, cognitive behavioral therapy (CBT), exercise, and self-help. None of these treatments have demonstrated consistent superiority to others in trials, although the administration of some (e.g. exercise) is admittedly very different from others. Even if it were useful to have a few of these treatments available in case one of them suddenly turned out to be harmful or because patients somehow developed resistance, it is difficult to justify so many.


Finally, non-inferiority trials present an ethical problem for the clinician. If the experimental treatment is at best roughly equal, but could be worse, then the best available therapy is the existing one. It is unclear whether the ethical clinician should allow her patient to risk receiving an inferior treatment.

Best wishes,

Jeremy
--

Jeremy Howick PhD, Msc, PGCert, DipSoc, BA
MRC/ESRC Postdoctoral Fellow
Centre for Evidence-Based Medicine
University of Oxford
Oxford OX3 7LF
United Kingdom
www.cebm.net
www.primarycare.ox.ac.uk/dept_staff/jeremy-howick/
eu.wiley.com/WileyCDA/WileyTitle/productCd-140519667X,descCd-authorInfo.html

From: "[log in to unmask]<mailto:[log in to unmask]>" <[log in to unmask]<mailto:[log in to unmask]>>
Reply-To: "[log in to unmask]<mailto:[log in to unmask]>" <[log in to unmask]<mailto:[log in to unmask]>>
Date: Fri, 15 Jul 2011 14:03:30 +0100
To: "[log in to unmask]<mailto:[log in to unmask]>" <[log in to unmask]<mailto:[log in to unmask]>>
Subject: solution to health care cost crisis: technical vs.philosphical..

In light of repeated discussion of unsustainable rise in health care costs that is threatening to undermine all other aspects of the way modern society functions, I attached the article from this morning NYT. The author argues that a technical solution to health care crisis is not feasible, but instead a solution lies in the way we deal with our own mortality. Understanding and accepting death as an integral aspect of human life- and hence not clinging to (expensive) medical interventions that are devised to “marginally extend the lives of the very sick” may provide the avenue to the current financial crisis that appears to be largely driven by health care costs.

Provocative and intriguing thoughts to which no one can remain indifferent….and I am looking forward to reading further insightful comments from the members of this group…

Best

Ben


Benjamin Djulbegovic, MD, PhD
Distinguished Professor
University of South Florida & H. Lee Moffitt Cancer Center & Research Institute
Department of Medicine
Chief, Division of Evidence-based Medicine and Health Outcomes Research
Co-Director of USF Clinical Translation Science Institute
Director of USF Center for Evidence-based Medicine and Health Outcomes Research


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